Hexavalent chromate, Cr(VI), is one of 33 compounds identified by the Environmental Protection Agency to pose the greatest potential health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate Cr(VI) is produced in many different industrial settings, with high levels of aerosolized forms of the compound generated. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in industrial workers exposed to inhaled particulate Cr(VI). Indeed, the National Institute of Occupational Safety and Health has mandated that allergic asthma should be listed as a significant adverse effect associated with occupational exposure to Cr(VI) compounds. To date, however, a direct causal association between inhalation of Cr(VI) and development of allergic asthma has not been established. One reason is that workers in the chromium industry are co-exposed to many occupational air pollutants, making it difficult to conclude which specific pollutant(s) is responsible for promoting asthma development. In addition, the majority of in vivo experimental studies looking at the effects of inhaled Cr(VI) compounds on respiratory function have been conducted using complex mixtures containing chromium particles, such as diesel fumes, rather than purified Cr(VI). Thus, the relative contribution of inhaled Cr(VI) to the development and/or severity of allergic asthma in chromium exposed workers remains unknown. The overarching hypothesis for the studies in the current application is that there is a causal association between inhalation of particulate hexavalent chromium and the development and/or exacerbation of allergic asthma. We propose to develop a new mouse model of particulate hexavalent chromate inhalation that will enable us to investigate the relationship between Cr(VI) exposure and the development of allergic asthma. Unlike previous animal models, our regimens will make use of immunological findings shown to favor the development of asthmatic responses both in humans and experimental animals. The generation of such an animal model will provide support for the working hypothesis that inhalation of particulate Cr(VI) can directly cause the development of chromium-specific allergic asthma. An alternative explanation for the reported association between asthma incidence and chromium exposure is that, rather than being a sensitizing allergen, Cr(VI) acts non-specifically to exacerbate allergic conditions established by other inhaled agents. Thus, we will also conduct studies to examine whether exposure to Cr(VI) increases the severity of ongoing allergic asthma. Positive findings from these studies will provide support for the working hypothesis that inhalation of particulate Cr(VI) exacerbates asthma induced by an unrelated allergen. To date, no animal studies have been conducted that directly investigate the relationship between exposure to particulate hexavalent chromium and the development of antigen-specific allergic asthma. Our proposed studies will be the first to establish whether the relationship between exposure to inhaled Cr(VI) and development of allergic asthma can be causal, or whether the relationship is more likely contributory. We have purposefully chosen to submit the current application under the Exploratory/Developmental R21 mechanism of funding because our studies involve the development of new animal models of Cr(VI) inhalation designed specifically to induce allergic asthma, rather than non- specific lung inflammation. This application also falls within the high-risk of an R21 because our working hypotheses are exploratory and have yet to be validated with preliminary data. However, if successful, the findings from the current studies will provide us with two new animal models to investigate the molecular relationship between inhalation of hexavalent chromium and asthma development, as well as the contribution of allergic inflammation to Cr(VI)-induced lung cancer. PUBLIC HEALTH RELEVANCE: Exposure to inhaled particulate chromates is associated with a high incidence of occupational allergic asthma and lung cancer in industrial workers. The current studies will develop a new animal model of hexavalent chromium induced allergic asthma. As part of these studies we will establish: (1) whether particulate hexavalent chromium can directly induce the development of allergic asthma, and (2) whether exposure to hexavalent chromates can exacerbate established allergic asthma. The findings from the proposed studies will provide the first complete characterization of lung immune responses to inhaled particulate chromates.